Alkylaminobenzothiazole and -benzoxazole derivatives

ABSTRACT

The present invention concerns the compounds of formula ##STR1## the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein X is O or S; n is 2, 3, 4 or 5; R 1  is hydrogen, C 1-6  alkyl, C 1-6  alkyloxy or halo; R 2  is hydrogen, C 1-6  alkyl, phenyl, phenylC 1-6  alkyl or phenylcarbonyl; R 3  and R 4  each independently are selected from hydrogen, halo, nitro, C 1-6  alkyl, C 1-6  alkyloxy, haloC 1-6  alkyl, aminosulfonyl, mono- or di(C 1-4  alkyl)aminosulfonyl; or R 3  and R 4  may also be taken together to form a bivalent radical of formula --CH═CH--CH═CH--; it further relates to processes for their preparation, compositions comprising them as well as their use as a medicine; compounds of formula (I) containing a radioactive isotope; a process of marking dopamine D 4  receptor sites; and a process for imaging an organ are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. § 371of PCT/EP97/02505 filed May 2, 1997, which claims priority from EP96.201.282.9, filed May 10, 1996.

The present invention concerns alkylaminobenzothiazoles and-benzoxazoles; it further relates to processes for their preparation,compositions comprising them, as well as their use as a medicine. Thecompounds of the present invention exhibit specific dopamine D₄ receptorantagonism and may particularly be useful as antipsychotics, especiallyin the treatment and/or prevention of psychotic disorders such asschizophrenia. In addition, the present invention concerns compounds offormula (I) containing a radioactive isotope; a process of markingdopamine D₄ receptor sites; and a process for imaging an organ.

It is generally accepted knowledge that dopamine receptors are importantfor many biochemical functions in the animal body. For example, alteredfunctions of these receptors not only participate in the genesis ofpsychosis, but also of anxiety, emesis, motoric functions, addiction,sleep, feeding, learning, memory, sexual behaviour, regulation ofimmunological responses and blood pressure. Since dopamine receptorscontrol a great number of pharmacological events, some of which are thusfar unknown, there is a possibility that compounds which exhibit aspecific binding affinity for the D₄ receptor may exert a wide range oftherapeutic effects in humans.

EP-A-0,335,586, published on Oct. 4, 1989, describes2-[4-(diarylmethyl)-1-piperazinyl)alkylamino]benzothiazoles and-benzoxazoles having antihistaminic and antiallergic activity.

The alkylaminobenzothiazoles and -benzoxazoles of the present inventionsurprisingly show a high degree of dopamine D₄ receptor bindingaffinity. Moreover, the present compounds have a selective affinity forthe dopamine D₄ receptor over other dopamine receptors in the humanbody. The subject compounds also show variable affinity for otherreceptors such as, for example, serotonin receptors, histaminereceptors, adrenergic receptors, cholinergic receptors and the σ-bindingsite.

The present invention concerns compounds having the formula ##STR2## theN-oxide forms, the pharmaceutically acceptable acid addition salts andstereochemically isomeric forms thereof, wherein

X is O or S;

n is 2, 3, 4 or 5;

R¹ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxy or halo;

R² is hydrogen, C₁₋₆ alkyl, phenyl, phenylC₁₋₆ alkyl or phenylcarbonyl;

R³ and R⁴ each independently are selected from hydrogen, halo, nitro,C₁₋₆ alkyl, C₁₋₆ alkyloxy, haloC₁₋₆ alkyl, aminosulfonyl, mono- ordi(C₁₋₄ alkyl)-aminosulfonyl; or

R³ and R⁴ may also be taken together to form a bivalent radical offormula --CH═CH--CH═CH--.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₄ alkyl defines straight and branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl,2-methylpropyl, 2,2-dimethylethyl and the like; C₁₋₆ alkyl is meant toinclude C₁₋₄ alkyl and the higher homologues thereof having 5 or 6carbon atoms such as, for example pentyl, 2-methylbutyl, hexyl,2-methylpentyl and the like; haloC₁₋₆ alkyl is defined aspolyhalosubstituted C₁₋₆ alkyl, in particular C₁₋₆ alkyl substitutedwith 1 to 6 halogen atoms, more in particular difluoro- ortrifluoromethyl.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. Said salts can be obtained by treating the base form of thecompounds of formula (I) with appropriate acids such as inorganic acids,for example, hydrohalic acid, e.g. hydrochloric or hydrobromic,sulfuric, nitric, phosphoric and the like acids; or organic acids, suchas, for example, acetic, hydroxy-acetic, propanoic, lactic, pyruvic,oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The N-oxides of the present compounds are meant to comprise thosecompounds of formula (I) wherein one or more nitrogen atoms are oxidizedto the so-called N-oxide.

The term "stereochemically isomeric forms" as used hereinbefore andhereinafter defines all the possible isomeric forms in which thecompounds of formula (I) may occur. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture,and in particular the racemic mixture, of all possible stereochemicallyisomeric forms, said mixtures containing all diastereomers andenantiomers of the basic molecular structure. Stereochemically isomericforms of the compounds of formula (I) and mixtures of such forms areobviously intended to be encompassed by formula (I).

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.For instance, compounds of formula (I) wherein R² is hydrogen may existin their corresponding tautomeric form.

An interesting group of compounds are those compounds of formula (I)wherein X is S and R² is hydrogen, C₁₋₆ alkyl, phenyl or phenylC₁₋₆alkyl.

Another interesting group of compounds are those compounds of formula(I) wherein X is O and R² is hydrogen, C₁₋₆ alkyl or phenylC₁₋₆ alkyl.

Also interesting compounds are those compounds of formula (I) wherein R³and R⁴ are selected from the goup consisting of hydrogen, nitro, halo,C₁₋₆ alkyl, C₁₋₆ alkyloxy and trifluoromethyl, or R³ and R⁴ are takentogether to form a bivalent radical of formula --CH═CH--CH═CH--.

Particular compounds are those interesting compounds wherein n is 2, 3or 4.

Preferred compounds are those compounds of formula (I) wherein X is S,R² is hydrogen, C₁₋₆ alkyl, phenyl or phenylC₁₋₆ alkyl, and n is 2.

Other preferred compounds are those compounds of formula (I) wherein R²and R³ are hydrogen and R⁴ is chloro.

Most preferred are the compounds

N-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine;

N-[2-(4-phenyl-1-piperazinyl)ethyl]-2-benzothiazolamine;

N-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine;

N-[2-[4-(4-bromophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine; theN-oxides, the stereoisomeric forms and the pharmaceutically acceptableacid addition salts thereof.

The compounds of the present invention can generally be prepared byN-alkylating an intermediate of formula (III) with an intermediate offormula (II) wherein W¹ represents an appropriate reactive leaving groupsuch as, for example, a halogen. ##STR3##

Said N-alkylation may be performed by stirring and heating the reactantsin a reaction-inert solvent such as ethanol, 2-ethoxyethanol, 1-butanol,methylisobutylketon or toluene, preferably in the presence of a suitablebase such as sodiumcarbonate, and optionally in the presence of acatalyst such as, for example, potassium iodide.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, trituration and chromatography.

Compounds of formula (I) wherein X is S, said compounds beingrepresented by formula (I-a), may be prepared by reacting anintermediate of formula (III) with an intermediate of formula (IV) in areaction-inert solvent such as, for example, tetra-hydrofuran, andsubsequently cyclizing the thus formed intermediate of formula (V) in areaction-inert solvent such as, for example, chloroform, and in thepresence of a suitable reagent such as, for example, thionylchloride.Alternatively, compounds of formula (I-a) can be prepared by directlymixing an intermediate of formula (III) with an intermediate of formula(IV) in a reaction-inert solvent, such as, for example, chloroform, inthe presence of a suitable reagent such as, for example,thionylchloride, thus forming in situ an intermediate of formula (V)which is immediately cyclized during the course of the reaction.##STR4##

The present compounds can also be prepared by N-alkylating anintermediate of formula (VI) with an intermediate of formula (VII)wherein W² is an appropriate leaving group such as, for example, ahalogen, optionally in a reaction inert solvent such as, for example,dimethylacetamide. ##STR5##

Alternatively, the compounds of formula (I) can be prepared byN-alkylating an intermediate of formula (XV) with an intermediate offormula (XVI) wherein W² is an appropriate leaving group such as, forexample, a halogen, in a reaction-inert solvent such as, for example,tetrahydrofuran, and, in the presence of a suitable base such as, forexample, sodium hydride or a functional equivalent thereof. ##STR6##

The compounds of formula (I) may be also converted into other compoundsof formula (I) following art-known transformation reactions. Forinstance, compounds of formula (I) wherein R² is hydrogen, saidcompounds being represented by formula (I-b), may be converted intocompounds of formula (I) wherein R² is other than hydrogen.

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydroperoxide. Suitable solvents are, for example, water,lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Intermediates and starting materials used in the above reactionprocedures are mostly known compounds which are commercially availableor may be prepared according to art-known procedures. For instance,intermediates of formula (XV) may be prepared according to the proceduredescribed in J. Chem. Soc., 1962, 230, and intermediates of formula(XVI) may be prepared according to the procedure as described in JP60202883.

The intermediates of formula (III) can generally be prepared byhydrolysis of a carbamate ester of formula (VIII) in a reaction-inertsolvent such as, for example, isopropanol and in the presence of asuitable base such as, for example, potassium hydroxide. It may furtherbe convenient to perform said reaction at reflux temperature. ##STR7##

Intermediates of formula (VIII) may be prepared by N-alkylating apiperazine derivative of formula (IX) with a carbamate ester of formula(X) wherein W³ is an appropriate leaving group such as, for example, ahalogen. ##STR8##

Said reaction may be performed by stirring and heating the reactants ina reaction-inert solvent such as, for example, 4-methyl-2-pentanone, inthe presence of a suitable base such as sodiumcarbonate, and optionallyin the presence of a catalytic amount of a potassium salt such as, forexample, potassium iodide.

Intermediates of formula (III) wherein R² is hydrogen, saidintermediates being represented by formula (III-a), can also be preparedby catalytic hydrogenation of a nitrile derivative of formula (XI) usinghydrogen in the presence of an appropriate catalyst such as, forexample, Raney-nickel. It may be convenient to perform said reaction ina reaction-inert solvent such as, for example, tetrahydrofuran ormethanol saturated with NH₃. ##STR9##

Intermediates of formula (XI) may be prepared by N-alkylating apiperazine derivative of formula (IX) with a nitrile derivative offormula (XII) wherein W⁴ is an appropriate leaving group such as, forexample, a halogen, in an analogous way as intermediates (VIII) wereprepared starting form intermediates (IX) and (X). ##STR10##

Alternatively, nitrile derivatives of formula (XI) wherein (n-1) is 2,said derivatives being represented by formula (XI-a), may be prepared byN-alkylating a piperazine derivative of formula (IX) with acrylonitrileby stirring and heating the reactants in a reaction-inert solvent suchas, for example, 2-propanol, and optionally in the presence of acatalytic amount of a quaternary ammonium salt such as, for example,N-methyl-N,N-dioctyl octanaminiumchloride. ##STR11##

Intermediates of formula (VII) may be prepared by first N-alkylating anintermediate of formula (XIII) with an intermediate of formula (II) andsubsequently replacing the hydroxy group of the thus obtainedintermediate of formula (XIV) by a suitable leaving group W⁴, such as,for example, chloro. For instance, intermediates of formula (XIV) may bereacted with thionylchloride to form an intermediate of formula (VII)wherein W⁴ is chloro. ##STR12##

An alternative way to prepare intermediates of formula (VII) includesthe N-alkylation of an intermediate of formula (XV) with an intermediateof formula (XVII) wherein LG is a leaving group such as bromo and W² isa leaving group as defined in intermediates of formula (VII) whereby LGis chosen as such that the substitution reaction with the intermediateof formula (XV) will preferentially occur on the carbon atom bearing theLG moiety. Said reaction is preferably performed in a reaction-inertsolvent in the presence of a suitable base such as, for example, sodiumhydride. ##STR13##

In a similar way, intermediates of formula (XVI) may be prepared byN-alkylating an intermediate of formula (IX) with an intermediate offormula (XVII). ##STR14##

Some of the compounds of formula (I) and some of the intermediates inthe present invention contain at least one asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Pure stereochemically isomeric forms of the compounds of formula (I) mayalso be obtained from the pure stereochemically isomeric forms of theappropriate intermediates and starting materials, provided that theintervening reactions occur stereospecifically. The pure and mixedstereochemically isomeric forms of the compounds of formula (I) areintended to be embraced within the scope of the present invention.

The compounds of formula (I), the N-oxides, the pharmaceuticallyacceptable acid addition salts and stereochemically isomeric formsthereof, are potent antagonists of the dopamine D₄ receptor, i.e. theyshow a high degree of dopamine D₄ receptor binding affinity thusinhibiting the binding of an endogeneous ligand, in particular dopamine,to the dopamine D₄ receptor, as is demonstrated in the pharmacologicalexample described hereinafter. The antagonistic effect of the binding ofthe present compounds to the dopamine D₄ receptor was confirmed insignal-transduction assays.

The present compounds show interesting activity in the so-called"differential reinforcement test low rate 72 seconds"-test (DRL-72)which is an in vivo test where most clinically active antidepressantsgiven at high doses show activity. In said test, rats can obtain food bypressing a lever only when they have waited a full 72 seconds betweentwo lever presses. The present D₄ antagonists induce a more efficientbehaviour of the rats whereas untreated animals find it difficult tocontrol their impulsive tendency to press the lever and to subordinateit to appropriate timing so as to maximize their award. The usefulnessof this DRL-72 test as a model for specific D₄ antagonists such as thepresent compounds is further supported by the fact that (a) Manki et al.(Journal of Affective Disorders 40 (1996), 7-13) found that there is asignificant association between the D₄ receptor gene polymorphism andmood disorders, and (b) by the fact that D₄ receptors are known to bemost dense in hippocampus, entorhinal and cerebral cortex in theprimates, humans as well as rodents.

Antagonizing the dopamine D₄ receptor will suppress or relieve a varietyof symptoms associated with phenomena induced by the activation, inparticular the excessive activation, of said receptor. Consequently, theability of the present compounds to alter dopamine D₄ mediatedneurotransmission makes them of potential use in the treatment and/orprevention of a variety of disorders associated therewith such as sleepdisorders, sexual disorders, thought disorders, impaired informationprocessing, psychosis, affective psychosis, nonorganic psychosis,personality disorders, psychiatric mood disorders, conduct and impulsedisorders, schizophrenic and schizoaffective disorders, polydipsia,bipolar disorders, dysphoric mania, anxiety and related disorders,gastrointestinal disorders, obesity, emesis, bacterial infections of theCNS such as meningitis, learning disorders, memory disorders,Parkinson's disease, depression, extrapyramidal side effects fromneuroleptic agents, neuroleptic malignant syndrome, hypothalamicpituitary disorders, congestive heart failure, chemical dependenciessuch as drug and alcohol dependencies, vascular and cardiovasculardisorders, ocular disorders, dystonia, tardive dyskinesia, Gilles De laTourette's syndrome and other hyperkinesias, dementia, ischemia,movement disorders such as akathesia, hypertension and diseases causedby a hyperactive immune system such as allergies and inflammation.

The compounds of the present invention distinctively show affinity forthe dopamine D₄ receptor in comparison with other dopamine receptorssuch as, for example, the dopamine D₂ receptor. Such a dissociationbetween dopamine D₄ receptor antagonizing activity and other dopaminereceptor activity may be of additional use in the treatment and/orprevention of the above-mentioned disorders. For example, Van Tol et al.(Nature 1991, 350, 610-614) suggested that compounds which can interactselectively with the dopamine D₄ receptor, whilst having a lesspronounced action at the dopamine D₂ receptor, might have the samebeneficial level of antipsychotic activity as classical antipsychoticswith the additional benefit of being less prone to the undesiredextrapyramidal or neuroendocrine side-effects of classicalantipsychotics. It is therefore that the present compounds areparticularly useful as antipsychotics, especially in the treatmentand/or prevention of psychotic disorders such as schizophrenia.

In addition to their potency to antagonize the dopamine D₄ receptor, thesubject compounds also show variable affinity for other receptors suchas, for example, serotonin receptors, histamine receptors, adrenergicreceptors, cholinergic receptors and the σ-binding site. For instance,some of the present compounds show a favourable binding affinity for theσ-binding site, the 5 HT_(1A) receptor and the α₂ -receptor.

In view of the usefulness of the subject compounds in the treatmentand/or prevention of disorders associated with the excessive activationof the dopamine D₄ receptor, in particular in the treatment of psychoticdisorders such as schizophrenia, the present invention provides a methodof treating warm-blooded animals suffering from such disorders, saidmethod comprising the systemic administration of a dopamine D₄ receptorantagonizing amount of a compound of formula (I), a N-oxide, astereo-chemically isomeric form or a pharmaceutically acceptable acidaddition salt thereof.

The present invention thus also relates to compounds of formula (I) asdefined hereinabove for use as a medicine. Further, the presentinvention also relates to the use of a compound of formula (I) for themanufacture of a medicament for treating psychotic disorders.

Another aspect of the present invention involves the ability of thepresent compounds to act as lipid lowering agents. Some of the presentcompounds of formula (I) were tested in animals and showed a markedlipid lowering effect rendering the present compounds useful agents inthe treatment or prophylaxis of hyperlipidemia or atherosclerosis.

The term "dopamine D₄ receptor antagonizing amount", as used herein,refers to an amount sufficient to inhibit the binding of an endogeneousligand, in particular dopamine, to the dopamine D₄ receptor. Those ofskill in the treatment of the disorders as mentioned hereinabove coulddetermine that an effective dopamine D₄ receptor antagonizing dailyamount would be from about 0.01 mg/kg to about 10 mg/kg body weight,more preferably from about 0.04 mg/kg to about 4 mg/kg body weight. Thecompounds may be administered on a regimen of 1 to 4 times per day.

In order to alleviate the symptoms of psychotic disorders such asschizophrenia without causing undesired side-effects, the dosage levelof the compound according to the invention is ideally selected such thatthe dose administered is effective in substantially completely blockingthe dopamine D₄ receptor while displaying a favourable dopamine D₂receptor occupancy causing no or negligible undesired extrapyramidal orneuroendocrine side-effects.

If desired, the compounds according to this invention may beco-administered with another antipsychotic, for example one producingits effects via one or more of the following mechanisms: dopamine D₂receptor blockade, 5-HT₂ receptor blockade, 5-HT_(1A) agonism and 5-HT₃antagonism. In such circumstances, an enhanced antipsychotic effect maybe envisaged without a corresponding increase in side-effects such asthose caused by, for example, strong dopamine D₂ receptor blockade; or acomparable antipsychotic effect with reduced side-effects mayalternatively be envisaged. Such co-administration may be desirablewhere a patient is already established on a, for example,anti-schizophrenic treatment regime involving conventionalanti-schizophrenic medicaments.

For administration purposes, the subject compounds may be formulatedinto various pharmaceutical forms. To prepare the pharmaceuticalcompositions of this invention, an effective dopamine D₄ receptorantagonizing amount of the particular compound, as acid addition salt orin its free base form, as the active ingredient is combined in intimateadmixture with a pharmaceutically acceptable carrier, which may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,percutaneously, or by parenteral injection. For example, in preparingthe compositions in oral dosage form, any of the usual pharmaceuticalmedia may be employed, such as, for example, water, glycols, oils,alcohols and the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable solutions containing compoundsof formula (I) may be formulated in an oil for prolonged action.Appropriate oils for this purpose are, for example, peanut oil, sesameoil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol estersof long chain fatty acids and mixtures of these and other oils.Injectable suspensions may also be prepared in which case appropriateliquid carriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewettable agent, optionally combined with suitable additives of anynature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment. Acid addition salts of the compounds of formula (I)due to their increased water solubility over the corresponding free baseform, are more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Due to their high degree of specificity to the dopamine D₄ receptor, thecompounds of formula (I) as defined above, are also useful to mark oridentify receptors, in particular dopamine D₄ receptors. To thispurpose, the compounds of the present invention need to be labelled, inparticular by replacing, partially or completely, one or more atoms inthe molecule by their radioactive isotopes. Examples of interestinglabelled compounds are those compounds having at least one halo which isa radioactive isotope of iodine, bromine or fluorine; or those compoundshaving at least one ¹¹ C-atom or tritium atom.

One particular group consists of those compounds of formula (I) whereinR¹ and/or R³ and/or R⁴ are a radioactive halogen atom. In principle, anycompound of formula (I) containing a halogen atom is prone forradiolabelling by replacing the halogen atom by a suitable isotope.Suitable halogen radioisotopes to this purpose are radioactive iodides,e.g. ¹²² I, ¹²³ I, ¹²⁵ I, 131I; radioactive bromides, e.g. ⁷⁵ Br, ⁷⁶ Br,⁷⁷ Br and ⁸² Br, and radioactive fluorides, e.g. ¹⁸ F. The introductionof a radioactive halogen atom can be performed by a suitable exchangereaction or by using any one of the procedures as described hereinaboveto prepare halogen derivatives of formula (I).

Preferred labelled compounds are those compounds of formula (I), whereinR¹ and/or R³ and/or R⁴ are ¹²³ I, ¹²⁵ I, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br or ¹⁸ F.

Another interesting form of radiolabelling is by substituting a carbonatom by a ¹¹ C-atom or the substitution of a hydrogen atom by a tritiumatom. For instance, introducing such a ¹¹ C-atom may be carried out byN-alkylating a compound of formula (I), wherein R² is hydrogen using a¹¹ C-labelled alkylating reagent.

Hence, said radiolabelled compounds of formula (I) can be used in aprocess of specifically marking dopamine D₄ receptor sites in biologicalmaterial. Said process comprises the steps of (a) radiolabelling acompound of formula (I), (b) administering this radiolabelled compoundto biological material and subsequently (c) detecting the emissions fromthe radiolabelled compound. The term biological material is meant tocomprise every kind of material which has a biological origin. More inparticular this term refers to tissue samples, plasma or body fluids butalso to animals, specially warm-blooded animals, or parts of animalssuch as organs. The radiolabelled compounds of formula (I) are alsouseful as agents for screening whether a test compound has the abilityto occupy or bind to a dopamine D₄ receptor site. The degree to which atest compound will displace a compound of formula (I) from the dopamineD₄ receptor site will show the test compound ability as either anagonist, an antagonist or a mixed agonist/antagonist of a dopamine D₄receptor. When used in in vivo assays, the radiolabelled compounds areadministered in an appropriate composition to an animal and the locationof said radiolabelled compounds is detected using imaging techniques,such as, for instance. Single Photon Emission Computerized Tomography(SPECT) or Positron Emission Tomography (PET) and the like. In thismanner the distribution of dopamine D₄ receptor sites throughout thebody can be detected and organs containing dopamine D₄ receptor sitessuch as, for example, the brain, can be visualized by the imagingtechniques mentioned hereinabove. This process of imaging an organ byadministering a radiolabelled compound of formula (I), which binds tothe dopamine D₄ receptor sites and detecting the emissions from theradioactive compound also constitutes a part of the present invention.

The following examples are intended to illustrate and not to limit thescope of the present invention.

Experimental Part A. Preparation of the Intermediate Compounds EXAMPLEA.1

a) A mixture of 1-(4-bromophenyl)piperazine (0.018 mol) and ethyl(2-chloroethyl)-carbamate (0.036 mol) was stirred for 2 hours at 130° C.Triethylamine (3 ml) was added and the mixture was stirred for 15minutes at 130° C. The reaction mixture was cooled to room temperature,CH₂ Cl₂ was added and the resulting mixture was washed with water. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5). The pure fractions werecollected and the solvent was evaporated, yielding 4.3 g (67.2%) ofethyl [2-[4-(4-bromophenyl)-1-piperazinyl]-ethyl]carbamate (interm. 1).

b) A mixture of intermediate (1) (0.029 mol) and potassium hydroxide(0.29 mol) in 2-propanol (200 ml) was stirred and refluxed for 8 hours.CH₂ Cl₂ was added. Water was added dropwise to dissolve thepotassium-salts. The organic layer was separated, dried, filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 90/10).The pure fractions were collected and the solvent was evaporated,yielding 3.8 g (46%) of 4-(4-bromophenyl)-1-piperazineethanamine(interm. 4).

In a similar way were prepared

4-(4-iodophenyl)-1-piperazineethanamine (interm. 11);

4-(1-naphtalenyl)-1-piperazinepentanamine (interm. 12);

4-(1-naphtalenyl)-1-piperazineethanamine (interm. 13);

4-(1-naphtalenyl)-1-piperazinepropanamine (interm. 14);

4-(4-nitrophenyl)-1-piperazinepropanamine (interm. 15);

4-(4-bromophenyl)-1-piperazinebutanamine (interm. 16); and

4-(4-bromophenyl)-1-piperazinepropanamine (interm. 17).

EXAMPLE A.2

a) A mixture of 1-(3,4-dichlorophenyl)piperazine (0.1 mol),5-chloropentanenitrile (0.13 mol), sodium carbonate (10 g) and potassiumiodide (0.1 g) in 4-methyl-2-pentanone (280 ml) was stirred and refluxedfor 10 hours. The reaction mixture was cooled, filtered and the filtratewas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5). The pure fractions werecollected and the solvent was evaporated, yielding 22.5 g (72%) of4-(3,4-dichlorophenyl)-1-piperazinepentanenitrile (interm. 2).

b) A mixture of intermediate (2) (0.072 mol) in tetrahydrofuran (250 ml)was hydrogenated with Raney nickel (2 g) as a catalyst. After uptake ofH₂, the catalyst was filtered off and the filtrate was evaporated. Theresidue was stirred in diisopropylether, filtered off over dicalite andthe filtrate was evaporated, yielding 20 g (88%) of4-(3,4-dichlorophenyl)-1-piperazinepentanamine (interm. 5).

In a similar way were prepared:

4-(2,4-dimethylphenyl)-1-piperazineethanamine(interm. 18);

4-(2,4-dimethylphenyl)-1-piperazinebutanamine (interm. 19);

4-(2,4-dimethylphenyl)-1-piperazinepentanamine (interm. 20);

4-(3,4-dichlorophenyl)-1-piperazinepropanamine (interm. 21);

4-(3,4-dichlorophenyl)-1-piperazinebutanamine (interm. 22); and

4-phenyl-1-piperazinepropanamine (interm. 23).

EXAMPLE A.3

A mixture of 1-(3,4-dichlorophenyl)piperazine (0.1 mol),2-propenenitrile (0.15 mol), and N-methyl-N,N-dioctyloctanaminiumchloride (1 ml) in 2-propanol (150 ml) was stirred andrefluxed for one hour. The solvent was evaporated and the residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃OH 95/5). The pure fractions were collected and the solvent wasevaporated. The residue was stirred in diisopropylether/acetonitrile10/1. The solvent was evaporated, yielding 28 g (98.5%) of4-(3,4-dichlorophenyl)-1-piperazinepropanenitrile (interm. 3).

EXAMPLE A.4

A mixture of 4-(3,4-dichlorophenyl)-1-piperazineethanamine (0.01 mol)and 4-methyl-1-isothiocyanatobenzene (0.01 mol) in tetrahydrofuran (300ml) was stirred at room temperature for 1 hour. The solvent wasevaporated. The residue was recrystallized from DIPE. The precipitatewas filtered off and dried. The product was used without furtherpurification, yielding 4.2 gN-(4-methylphenyl)-N'-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]thiourea(interm. 6).

EXAMPLE A.5

a) A mixture of 5-(methylamino)pentanol (0.23 mol),2-chlorobenzothiazole (0.3 mol), sodium carbonate (0.4 g) and potssiumiodide (catalytic quantity) in methylisobutylketon (1000 ml) was stirredand refluxed overnight. The reaction mixture was cooled, washed withwater, dried, filtered and the filtrate was evaporated. The residue wasstirred in water, acidified with HCl, stirred, washed withdiisopropylether, and the acidic layer was alkalized with NH₄ OH. Thismixture was extracted twice with CH₂ Cl₂. The separated organic layerwas dried, filtered, and the solvent was evaporated, yielding 56 g ofN-(5-hydroxypentyl)-N-methyl-2-benzothiazolamine (interm. 7).

b) Thionylchloride (60 ml) was stirred in CHCl₃ (400 ml). A solution ofintermediate (7) (0.22 mol) in CHCl₃ (200 ml) was added dropwise. Themixture was stirred at room temperature overnight. The solvent wasevaporated and the residue was dissolved in CH₂ Cl₂, washed with water,dried, filtered and the solvent was evaporated, yielding 65 g ofN-(5-chloropentyl)-N-methyl-2-benzothiazolamine (interm. 8).

EXAMPLE A.6

A mixture of 1-(3,4-dichlorophenyl)-piperazine (0.05 mol),1-bromo-2-chloroethane (0.1 mol) and triethylamine (0.05 mol) wasstirred for 30 minutes at 100° C. The mixture was cooled, thenpartitioned between CH₂ Cl₂ and water. The layers were separated. Theorganic phase was filtered over dicalite. The organic filtrate wasdried, filtered and the filtrate was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃OH 98/2). The pure fractions were collected and the solvent wasevaporated, yielding 5.2 g (35%) of4-(2-chloroethyl)-1-(3,4-dichlorophenyl)-piperazine (interm. 9).

EXAMPLE A.7

Sodium hydride (0.05 mol) was added portionwise to a solution ofN-phenyl-2-benzothiazolamine, prepared according to the proceduredescribed in J. Chem. Soc, 1962, 230, (0.05 mol) in tetrahydrofuran (200ml). The mixture was stirred for 15 minutes. A solution of1-bromo-4-chlorobutane (0.05 mol) in tetrahydrofuran (50 ml) was addeddropwise and the resulting reaction mixture was stirred and refluxed for48 hours. The mixture was cooled, and the solvent was evaporated. Theresidue was partitioned between water and CH₂ Cl₂. The organic layer wasseparated, dried, filtered and the solvent evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂). Thedesired fractions were collected and the solvent was evaporated,yielding 10.4 g (66%) of N-(4-chlorobutyl)-N-phenyl-2-benzothiazolamine(interm. 10).

N-(5-chloropentyl)-N-phenyl-2-benzothiazolamine (interm. 24) wasprepared similarly.

B. Preparation of the Final Compounds EXAMPLE B.1

a) A mixture of intermediate (5) (0.015 mol), 2-chlorobenzthiazole(0.016 mol) and sodium carbonate (4 g) in toluene (150 ml) was stirredand refluxed overnight. The reaction mixture was cooled and filtered.The filtrate was evaporated and the residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5). Thedesired fractions were collected, the solvent was evaporated and theresidue was crystallized from CH₃ CN. The precipitate was filtered offand dried, yielding 2.3 g (34%) ofN-[5-[4-(3,4-dichlorophenyl)-1-piperazinyl]pentyl]-2-benzothiazolamine(comp. 1).

b) N-[3-[4-phenyl-1-piperazinyl]propyl]-2-benzothiazolamine (comp. 5)was prepared according to the same procedure as described in exampleB.1.a) but using ethanol instead of toluene.

c) N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]butyl]-2-benzothiazolamine(comp. 26) was prepared according to the same procedure as described inexample B.1.a) but using methylisobutylketon instead of toluene.

d)N-[3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]propyl]-2-benzothiazolamine(comp. 27) was prepared according to the same procedure as described inexample B.1.a) but using 2-ethoxyethanol instead of toluene.

e)N-[4-[4-(3,4-dichlorophenyl)-1-piperazinyl]butyl]-6-methyl-2-benzothiazolamine(comp. 52) was prepared according to the same procedure as described inexample B.1.d) but a catalytic amount of potassium iodide was added tothe starting reaction mixture.

EXAMPLE B.2

4-(3,4-dichlorophenyl)-1-piperazinebutanamine (0.0085 mol), preparedaccording to the procedure described in example A.5, and2-chloro-6-methoxybenzothiazole (0.0043 mol) was stirred at 120° C. for1 hour. The mixture was cooled to room temperature, diluted with CH₂ Cl₂and converted into the free base with NH₄ OH. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂ Cl₂ /CH₃ OH 90/10). The pure fractions were collected and thesolvent was evaporated. The residue was converted into the(E)-2-butenedioic acid salt (1:1). The precipitate was filtered off anddried, yielding 1.1 g (44%) ofN-[4-[4-(3,4-dichlorophenyl)-1-piperazinyl]butyl]-6-methoxy-2-benzothiazolamine(E)-2-butenedioate(1:1) (comp. 42).

EXAMPLE B.3

Intermediate (6) (0.01 mol) was dissolved in CHCl₃ (30 ml). The mixturewas cooled to 0° C. Thionyl chloride (11.5 ml) was added dropwiseslowly. The mixture was allowed to warm slowly to room temperature andthen stirred for 30 minutes. The solvent was evaporated and the residuewas washed with a small amount of HCl/2-propanol in 2-propanone,filtered, washed with 2-propanone and converted into the free base witha NH₄ OH solution. The precipitate was filtered off and purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5).The pure fractions were collected and the solvent was evaporated,yielding: 0.7 g (16.7%) ofN-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]-6-methyl-2-benzothiazolamine(comp. 53).

EXAMPLE B.4

A mixture of 4-(3,4-dichlorophenyl)-1-piperazinepropanamine (0.009 mol),prepared according to the procedure described in Example A.5, and1-isothiocyanato-4-methoxybenzene (0.009 mol) in CHCl₃ (100 ml) wasstirred for one hour at room temperature, then cooled to 0° C. on anice-bath. Thionylchloride (30 ml) was added dropwise and the resultingreaction mixture was allowed to slowly warm to room temperature. Thereaction mixture was stirred for 3 hours at 60° C. The mixture wascooled to room temperature and the resulting precipitate was filteredoff, stirred in boiling 2-propanone, filtered off, then dried. Thisfraction was converted into the free base by addition of aqueousammonia. The mixture was extracted with CH₂ Cl₂. The separated organiclayer was dried, filtered and the solvent evaporated. The residue wascrystallized from CH₃ CN, filtered off, dissolved in 2-propanone andconverted into the hydrochloric acid salt (1:2) with HCl/2-propanol. Theprecipitate was filtered off and dried, yielding 1.6 g (34%) ofN-[3-[4-(3,4-dichlorophenyl)-1-piperazinyl]propyl]-6-methoxy-2-benzothiazolaminedihydrochloride (comp. 72).

EXAMPLE B.5

A mixture of compound (1) (0.01 mol), chloromethylbenzene (5 ml) andsodium hydride (0.015 mol; 60% solution) in tetrahydrofuran (200 ml) wasstirred and refluxed for 8 hours. The reaction mixture was cooled and afew drops of water were added. The solvent was evaporated. The residuewas partitioned between water and CH₂ Cl₂. The organic layer wasseparated, washed with water, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /ethylacetate 70/30). The pure fractionswere collected and the solvent was evaporated. The residue was dissolvedin 2-propanol and converted into the (E)-2-butenedioic acid salt (1:1)with (E)-2-butenedioic acid (1 g). The mixture was boiled, then stirredovernight at room temperature. The precipitate was filtered off anddried, yielding 2.70 g (41%) ofN-[5-[4-(3,4-dichlorophenyl)-1-piperazinyl]pentyl]-N-phenylmethyl-2-benzothiazolamine(E)-2-butenedioate(1:1) (comp. 112).

EXAMPLE B.6

A mixture of compound (3) (0.01 mol), sodium carbonate (4 g) andbenzoylchloride (0.01 mol) in chloroform (150 ml) andN,N-dimethylformamide (1 drop) was stirred and refluxed for 4 hours. Themixture was filtered warm and the filtrate was washed with water. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified over silica gel on a glass filter(eluent: CH₂ Cl₂ /ethanol 95/5). The pure fractions were collected andthe solvent was evaporated. The residue was crystallized from CH₃ CN.The precipitate was filtered off and dried, yielding 4.8 g (92.5%) ofN-(2-benzothiazolyl)-N-[3-[4-(3,4-dichlorophenyl)-1-piperazinyl]propyl]benzamide (comp. 99).

EXAMPLE B.7

A mixture of 1-(3,4-dichlorophenyl)piperazine (0.03 mol) andintermediate (8) (0.02 mol) in dimethylacetamide (2 ml) was stirred for2 hours at 120-130° C. The reaction mixture was cooled, dissolved in CH₂C₂, washed with aqueous ammonia, dried, filtered, and the filtrate wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 98/2), then repurified (eluent: CH₂Cl₂ /ethylacetate 50/50). The pure fractions were collected and thesolvent was evaporated. The residue was dissolved in 2-propanol andconverted into the (E)-2-butenedioic acid salt (1:1) with(E)-2-butenedioic acid (2 g). The mixture was boiled, then stirred atroom temperature. The precipitate was filtered off and dried, yielding6.60 g (57%) ofN-[5-[4-(3,4-dichlorophenyl)-1-piperazinyl]pentyl]-2-benzothiazolamine(E)-2-butenedioate(1:1) (comp. 110).

EXAMPLE B.8

Compound 12 (0.0058 mol) was dissolved in warm ethanol (75 ml).(E)-2-Butenedioic acid (0.0058 mol) was added and the resulting mixturewas stirred until complete dissolution. The mixture was allowed to coolto room temperature with stirring. The precipitate was filtered off anddried, yielding 2.03 g (80%) ofN-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine.(E)-2-butenedioate (2:1) (comp. 127).

EXAMPLE B.9

Compound 2 (0.015 mol) was dissolved in tetrahydrofuran (200 ml). Sodiumhydride (0.02 mol) was added. The mixture was stirred for 15 minutes atroom temperature. Dimethyl sulphate (0.015 mol) was added and theresulting reaction mixture was stirred for 4 hours at room temperature.The solvent was evaporated and the residue was purified over silica gel(eluent: ethylacetate/CH₃ OH/CH₂ Cl₂ 30/0/70, upgrading to 28/2/70). Thepure fractions were collected and the solvent was evaporated. Theresidue was dissolved in 2-propanol and converted into the(E)-2-butenedioic acid salt (1:1) with (E)-2-butenedioic acid (0.8 g).The mixture was boiled, then stirred overnight at room temperature. Theprecipitate was filtered off and dried, yielding 1.80 g (23%) ofN-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]-N-methyl-2-benzothiazolamine (E)-2-butenedioate(1:1) (comp. 117).

EXAMPLE B.10

A mixture of 4-(4-chlorophenyl)-1-piperazineethanamine (0.01 mol) and1-isothiocyanato-2-methoxybenzene (0.01 mol) in CCl₄ (100 ml) wasstirred for 1 hour at room temperature. Br₂ in CCl4 (0.01 mol in 10 ml)was added and the reaction mixture was stirred and refluxed for 1 hour.The reaction mixture was cooled to room temperature, diluted with CH₂Cl₂, and aqueous NH₃ was added. The organic layer was dried, filtered,and the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5). The purefractions were collected and the solvent was evaporated. The residue wasconverted into the hydrochloric acid salt (1:2). The precipitate wasfiltered off and dried, yielding 0.4 g (8%) ofN-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-7-methoxy-2-benzothiazolaminehydrochloride (1:2) hydrate (1:1) (comp. 143).

EXAMPLE B.11

N-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-6-fluoro-2-benzothiazolamine(comp 141) was prepared according to the procedure described in exampleB.10 but using SOCl₂ in CHCl₃ instead of Br₂ in CCl₄.

EXAMPLE B.12

N-phenyl-2-benzothiazolamine, prepared according to the proceduredescribed in J. Chem. Soc, 1962, 230, (0.03 mol) was dissolved intetrahydrofuran (100 ml). Sodium hydride (0.03 mol) was addedportionwise. The mixture was stirred for 15 minutes. A solution ofintermediate 9 (0.018 mol) in tetrahydrofuran (50 ml) was added. Theresulting reaction mixture was stirred and refluxed overnight. Thereaction mixture was cooled and the solvent was evaporated. The residuewas dissolved in CH₂ Cl₂. The organic solution was washed with water,dried, filtered, and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂/ethylacetate 90/10). The desired fractions were collected and thesolvent was evaporated. The residue was dissolved in 2-propanol andconverted into the (E)-2-butenedioic acid salt (1:1) with(E)-2-butenedioic acid (1.5 g). The mixture was boiled, then allowed tocool to room temperature. The precipitate was filtered off and dried,yielding 3.66 g (94%) ofN-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]-N-phenyl-2-benzothiazolamine(E)-2-butenedioate (1:1) (comp. 114).

The following compounds were prepared according to one of the aboveexamples.

                  TABLE 1                                                         ______________________________________                                          #STR15##                                                                      Comp.   Ex.                                                                   No. No. n R.sup.1 R.sup.3 R.sup.4 Physical data                             ______________________________________                                         1    B.1.a  5     H     3-Cl  4-Cl  mp. 128.8° C.                        2 B.1.a 2 H 3-Cl 4-Cl mp. 159.6° C.                                    3 B.1.a 3 H 3-Cl 4-Cl mp. 139.1° C.                                    4 B.1.a 4 H 3-Cl 4-Cl mp. 156.2° C.                                    5 B.1.b 3 H H H --                                                            6 B.1.b 2 H H H --                                                            7 B.1.b 3 H 3-Cl H --                                                         8 B.1.b 4 H H H --                                                            9 B.1.b 4 H 3-Cl H --                                                         10 B.1.b 3 H 4-Cl H --                                                        11 B.1.b 4 H 4-Cl H --                                                        12 B.1.b 2 H 4-Cl H --                                                        13 B.1.b 2 H 3-Cl H --                                                        14 B.1.b 4 H 4-Br H --                                                        15 B.1.b 3 H 4-Br H --                                                        16 B.1.b 2 H 4-Br H --                                                        17 B.1.a 3 H 2-OCH.sub.3 H --                                                 18 B.1.a 2 H 2-OCH.sub.3 H (E)-2-butenedioate                                      (1:1)                                                                    19 B.1.c 2 H 3-OCH.sub.3 H (E)-2-butenedioate                                      (1:1)                                                                    20 B.1.c 3 H 3-OCH.sub.3 H (E)-2-butenedioate                                      (1:1)                                                                    21 B.1.c 2 H 4-OCH.sub.3 H --                                                 22 B.1.c 3 H 4-OCH.sub.3 H --                                                 23 B.1.c 2 H 3-OCH.sub.3 4-OCH.sub.3 --                                       24 B.1.c 3 H 3-OCH.sub.3 4-OCH.sub.3 --                                       25 B.1.c 3 H 4-F H --                                                         26 B.1.c 4 H 4-OCH.sub.3 H --                                                 27 B.1.d 3 H 3-CF.sub.3 H --                                                  28 B.1.d 5 H 2-F H --                                                         29 B.1.c 5 H 4-OCH.sub.3 H --                                                 30 B.1.d 5 H 2-OCH.sub.3 H --                                                 31 B.1.d 4 H 3-OCH.sub.3 H (E)-2-butenedioate                                      (1:1)                                                                    32 B.1.c 2 H 2-F H (E)-2-butenedioate                                              (2:3)                                                                    33 B.1.c 3 H 2-F H --                                                         34 B.1.c 4 H 4-F H --                                                         35 B.1.c 4 H 2-F H --                                                         36 B.1.d 5 H 3-OCH.sub.3 H (E)-2-butenedioate                                      (2:1)                                                                    37 B.1.d 4 H 3-CF.sub.3 H (E)-2-butenedioate                                       (2:3)                                                                    38 B.1.d 5 H 3-CF.sub.3 H (E)-2-butenedioate                                       (1:1)                                                                    39 B.1.d 2 H 3-CF.sub.3 H (E)-2-butenedioate                                       (1:1)                                                                    40 B.1.d 2 H 4-CH.sub.3 H --                                                  41 B.2 2 6-Cl 3-Cl 4-Cl --                                                    42 B.2 4 6-OCH.sub.3 3-Cl 4-Cl (E)-2-butenedioate                                  (1:1)                                                                    43 B.1.c 2 H 4-F H --                                                         44 B.1.d 2 H 2-CH.sub.3 6-CH.sub.3 --                                         45 B.4 3 6-CH.sub.3 3-Cl 4-Cl --                                              46 B.1.d 3 H 2-CH.sub.3 6-CH.sub.3 --                                         47 B.1.d 4 H 2-CH.sub.3 6-CH.sub.3 --                                         48 B.1.d 5 H 2-CH.sub.3 6-CH.sub.3 --                                         49 B.1.d 2 H 2-CH.sub.3 5-CH.sub.3 --                                         50 B.1.d 4 H 2-CH.sub.3 5-CH.sub.3 --                                         51 B.1.e 2 6-OCH.sub.3 3-Cl 4-Cl 2 HCl                                        52 B.1.e 4 6-CH.sub.3 3-Cl 4-Cl --                                            53 B.3 2 6-CH.sub.3 3-Cl 4-Cl --                                              54 B.1.d 5 H 4-F H --                                                         55 B.1.d 5 H 2-CH.sub.3 5-CH.sub.3 --                                         56 B.1.e 4 6-Cl 3-Cl 4-Cl --                                                  57 B.1.e 5 6-F 3-Cl 4-Cl --                                                   58 B.1.d 3 H 4-CH.sub.3 H --                                                  59 B.1.d 5 H 4-CH.sub.3 H --                                                  60 B.1.d 4 H 4-CH.sub.3 H --                                                  61 B.1.d 2 H 2-CH.sub.3 3-CH.sub.3 --                                         62 B.1.e 5 6-CH.sub.3 3-Cl 4-Cl --                                            63 B.1.e 5 6-OCH.sub.3 3-Cl 4-Cl --                                           64 B.1.d 3 H 2-CH.sub.3 3-CH.sub.3 --                                         65 B.1.d 4 H 2-CH.sub.3 3-CH.sub.3 --                                         66 B.1.e 5 6-Cl 3-Cl 4-Cl --                                                  67 B.1.e 4 6-F 3-Cl 4-Cl --                                                   68 B.1.d 3 H 2-OCH.sub.3 4-OCH.sub.3 --                                       69 B.1.d 5 H 2-CH.sub.3 3-CH.sub.3 --                                         70 B.1.d 4 H 3-CH.sub.3 H --                                                  71 B.1.d 2 H 2-OCH.sub.3 4-OCH.sub.3 --                                       72 B.4 3 6-OCH.sub.3 3-Cl 4-Cl 2 HCl                                          73 B.1.d 4 H 2-OCH.sub.3 H (E)-2-butenedioate                                      (1:1)                                                                    74 B.1.d 3 H 3-CH.sub.3 H (E)-2-butenedioate                                       (1:1)                                                                    75 B.1.d 2 H 3-CH.sub.3 4-CH.sub.3 --                                         76 B.1.d 3 H 3-CH.sub.3 4-CH.sub.3 --                                         77 B.1.d 4 H 3-CH.sub.3 4-CH.sub.3 --                                         78 B.3 2 7-F 3-Cl 4-Cl --                                                     79 B.1.d 5 H 2-Cl H (E)-2-butenedioate                                             (2:3)                                                                    80 B.1.e 3 6-Cl 3-Cl 4-Cl --                                                  81 B.1.e 3 6-F 3-Cl 4-Cl --                                                   82 B.1.d 4 H 2-Cl H --                                                        83 B.1.d 5 H 3-CH.sub.3 4-CH.sub.3 --                                         84 B.1.d 2 H 2-Cl H (E)-2-butenedioate                                             (1:1)                                                                    85 B.1.d 3 H 2-Cl H                                                           86 B.1.d 5 H 3-CH.sub.3 H                                                     87 B.1.d 2 H 3-CH.sub.3 H (E)-2-butenedioate                                       (1:1)                                                                    88 B.1.d 3 H 2-CH.sub.3 5-CH.sub.3 --                                         89 B.1.d 3 H 2-CH.sub.3 4-CH.sub.3 --                                         90 B.1.d 2 H 2-CH.sub.3 H --                                                  91 B.1.d 3 H 2-CH.sub.3 H --                                                  92 B.1.d 4 H 2-CH.sub.3 H --                                                  93 B.1.d 5 H 2-CH.sub.3 H --                                                 122 B.1.d 2 H 2-CH.sub.3 4-CH.sub.3 --                                        123 B.1.d 4 H 2-CH.sub.3 4-CH.sub.3 --                                        124 B.1.d 5 H 2-CH.sub.3 4-CH.sub.3 --                                        125 B.1.d 3 H 4-NO.sub.2 H --                                                 126 B.8 2 H 4-Br H (E)-2-butenedioate                                               (2:1)                                                                   127 B.8 2 H 4-Cl H --                                                         128 B.1.e 2 H 4-I H --                                                        129 B.1.e 2 6-OCH.sub.3 4-Cl H (E)-2-butenedioate                                   (2:1)                                                                   130 B.1.e 2 6-F 4-Cl H --                                                     131 B.8 2 H 4-Cl H HBr (1:2)                                                  132 B.8 2 H 4-Cl H ethanedioate (1:1)                                         133 B.8 2 H 4-Cl H (S)-hydroxybutene-                                               dioate (1:1)                                                            134 B.8 2 H 4-Cl H H.sub.2 O (1:2)/HCl (1:1)                                  135 B.8 2 H 4-Cl H (+)-[R-(R*,R*)]-2,3-                                             dihydroxybutenedioate                                                         (1:1)                                                                   136 B.11 2 7-CH.sub.3 4-Cl H --                                               137 B.11 2 5-Cl 4-Cl H --                                                     138 B.11 2 5-CH.sub.3 4-Cl H --                                               139 B.11 2 5-OH 4-Cl H --                                                     140 B.11 2 6-OH 4-Cl H HCl (1:3)                                              141 B.11 2 5-F 4-Cl H --                                                      142 B.11 2 4-F 4-Cl H HCl (1:2)                                               143 B.10 2 4-OCH.sub.3 4-Cl H HCl (1:2)/H.sub.2 O (1:1)                       144 B.1.e 2 6-CH.sub.3 4-Cl H (E)-2-butenedioate                                    (1:1)                                                                   145 B.1.e 2 6-Cl 4-Cl H --                                                    146 B.11 2 4-Cl 4-Cl H HCl (1:3)                                              147 B.11 2 4-CH.sub.3 4-Cl H (E)-2-butenedioate                                     (2:1)                                                                 ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                          #STR16##                                                                      Comp. No.   Ex. No.  n    R.sup.3                                                                             R.sup.4                                                                             Physical data                         ______________________________________                                        94        B.2      4      3-Cl  4-Cl  --                                        95 B.2 5 3-Cl 4-Cl --                                                         96 B.2 2 3-Cl 4-Cl --                                                         97 B.2 3 3-Cl 4-Cl --                                                       ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                          #STR17##                                                                      Comp. No. Ex. No. n    R.sup.2  Physical data                               ______________________________________                                         98     B.6     2      phenylcarbonyl                                                                         (E)-2-butenedioate (1:1)                         99 B.6 3 phenylcarbonyl --                                                   100 B.1.a 3 methyl --                                                         101 B.1.a 2 methyl --                                                         102 B.7 4 methyl --                                                           103 B.5 3 1-butyl (E)-2-butenedioate (2:1)                                    104 B.5 3 phenylmethyl (E)-2-butenedioate (1:1)                               105 B.5 2 phenylmethyl (E)-2-butenedioate (2:1)                               106 B.5 2 phenylmethyl (E)-2-butenedioate (1:1)                               107 B.5 2 1-butyl (E)-2-butenedioate (1:1)                                    108 B.5 4 phenylmethyl (E)-2-butenedioate (1:1)                               109 B.5 4 1-butyl (E)-2-butenedioate (2:1)                                    110 B.7 5 methyl (E)-2-butenedioate (1:1)                                     111 B.5 5 1-butyl (E)-2-butenedioate (1:1)                                    112 B.5 5 phenylmethyl (E)-2-butenedioate (1:1)                               113 B.12 3 phenyl (E)-2-butenedioate (1:1)                                    114 B.12 2 phenyl (E)-2-butenedioate (1:1)                                    115 B.7 4 phenyl (E)-2-butenedioate (2:1)                                     116 B.7 5 phenyl (E)-2-butenedioate (1:1)                                     117 B.9 2 methyl (E)-2-butenedioate (1:1)                                   ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                          #STR18##                                                                       -                                                                              Comp. No.  Ex. No.   n    Physical data                                   ______________________________________                                        118        B.1.d     4      (E)-2-butenedioate (2:1)                            119 B.1.d 2 (E)-2-butenedioate (1:1)                                          120 B.1.d 3 --                                                                121 B.1.d 5 (E)-2-butenedioate (2:1)                                        ______________________________________                                    

Table 5 lists both the experimental (column heading "exp") andtheoretical (column heading "theor") elemental analysis values forcarbon, hydrogen and nitrogen of the compounds as prepared in theexperimental part hereinabove.

                  TABLE 5                                                         ______________________________________                                        Comp     Carbon     Hydrogen     Nitrogen                                     No.      exp    theor   exp   theor  exp  theor                               ______________________________________                                        3        56.04  57.01   5.33  5.26   12.92                                                                              13.30                                 11 62.11 62.90 6.11 6.28 13.65 13.97                                          12 61.25 61.20 5.59 5.68 15.05 15.02                                          13 61.25 61.20 5.61 5.68 15.01 15.02                                          16 54.56 54.68 4.80 5.07 13.32 13.42                                          17 65.25 65.94 6.88 6.85 14.54 14.65                                          19 59.79 59.49 5.87 5.82 11.65 11.56                                          20 59.80 60.22 5.85 6.06 11.09 11.24                                          21 65.31 65.19 6.44 6.56 15.21 15.20                                          22 66.03 65.94 7.02 6.85 14.76 14.65                                          23 62.98 63.29 6.47 6.58 14.06 14.06                                          24 63.90 64.05 6.99 6.84 13.52 13.58                                          25 64.74 64.84 6.30 6.26 15.09 15.12                                          26 66.52 66.63 7.23 7.12 14.10 14.13                                          28 65.99 66.30 6.85 6.83 13.97 14.06                                          29 67.24 67.28 7.83 7.36 13.75 13.65                                          30 67.28 67.28 7.41 7.36 13.67 13.65                                          31 61.01 60.92 6.31 6.29 11.07 10.93                                          32 56.42 56.59 5.10 5.13 10.33 10.56                                          33 64.51 64.84 5.96 6.26 14.90 15.12                                          34 65.54 65.60 6.50 6.55 14.53 14.57                                          35 64.98 65.60 6.52 6.55 14.46 14.57                                          36 63.98 64.08 6.91 6.88 12.13 11.96                                          37 55.29 55.26 5.14 5.13 9.24 9.21                                            38 57.44 57.44 5.62 5.53 10.04 9.92                                           39 54.89 55.17 4.70 4.82 10.56 10.72                                          40 68.29 68.15 6.92 6.86 16.08 15.89                                          41 51.37 51.65 4.08 4.33 12.54 12.68                                          42 53.40 53.70 5.27 5.20 9.33 9.63                                            43 63.77 64.02 5.98 5.94 15.48 15.72                                          44 68.49 68.82 7.07 7.15 15.21 15.29                                          45 58.05 57.93 5.43 5.56 12.83 12.87                                          46 69.16 69.44 7.28 7.42 14.83 14.72                                          47 69.87 70.01 7.59 7.66 14.18 14.20                                          48 70.39 70.55 7.98 7.89 13.70 13.71                                          50 69.69 70.01 7.63 7.66 14.24 14.20                                          51 47.02 47.07 4.52 4.74 10.83 10.98                                          52 58.76 58.79 5.84 5.83 12.44 12.47                                          53 56.97 57.01 5.14 5.26 13.26 13.30                                          54 64.62 66.30 6.73 6.83 13.95 14.06                                          55 70.57 70.55 8.19 7.89 13.77 13.71                                          56 53.47 53.68 4.97 4.93 11.93 11.92                                          57 56.63 56.53 5.32 5.39 11.97 11.99                                          58 68.44 68.82 7.31 7.15 15.48 15.29                                          59 69.77 70.01 7.53 7.66 14.03 14.20                                          60 69.41 69.44 7.48 7.42 14.61 14.72                                          61 68.57 68.82 7.08 7.15 14.90 15.29                                          62 59.39 59.60 5.95 6.09 11.95 12.09                                          63 57.61 57.62 6.06 5.89 11.68 11.69                                          64 69.41 69.44 7.37 7.42 14.51 14.72                                          65 69.72 70.01 7.62 7.66 14.42 14.20                                          66 54.65 54.61 5.20 5.21 11.50 11.58                                          67 55.26 55.63 4.96 5.11 12.19 12.36                                          68 63.43 64.05 6.88 6.84 13.73 13.58                                          69 69.50 70.55 7.78 7.89 13.72 13.71                                          70 68.94 69.44 7.74 7.42 15.02 14.72                                          71 63.44 63.29 6.58 6.58 14.08 14.06                                          72 48.04 48.10 4.96 5.00 10.51 10.69                                          73 61.03 60.92 6.53 6.29 10.80 10.93                                          74 62.21 62.22 6.15 6.27 11.51 11.61                                          75 67.90 68.82 7.13 7.15 15.10 15.29                                          76 69.15 69.44 7.23 7.42 14.72 14.72                                          77 68.57 70.01 7.66 7.66 13.89 14.20                                          78 53.33 53.65 4.89 4.50 13.09 13.17                                          80 52.54 52.70 4.41 4.64 12.28 12.29                                          81 54.83 54.67 5.04 4.82 12.85 12.75                                          83 70.58 70.55 7.96 7.89 13.88 13.71                                          84 55.94 56.49 5.03 5.15 11.20 11.46                                          85 62.26 62.08 5.93 5.99 14.54 14.48                                          86 69.74 70.01 7.67 7.66 14.10 14.20                                          88 67.75 69.44 7.19 7.42 14.05 14.72                                          94 59.95 60.15 5.75 5.77 13.34 13.36                                          95 60.62 60.97 6.16 6.05 12.80 12.93                                          96 58.43 58.32 5.19 5.15 14.58 14.32                                          97 59.48 59.27 5.44 5.47 14.04 13.82                                          98 57.06 57.42 4.33 4.50 8.76 8.93                                            99 61.59 61.71 5.05 4.99 10.62 10.66                                          100 57.82 57.93 5.44 5.56 12.83 12.87                                         101 57.02 57.01 5.01 5.26 13.21 13.30                                         102 58.64 58.79 5.85 5.83 12.34 12.47                                         103 58.28 58.31 6.01 6.02 10.35 10.46                                         104 59.32 59.33 5.27 5.14 8.94 8.93                                           105 60.33 60.54 5.09 5.08 10.05 10.09                                         106 58.75 58.73 4.92 4.93 8.93 9.13                                           107 55.82 55.96 5.41 5.57 9.58 9.67                                           108 59.88 59.90 5.36 5.34 8.71 8.73                                           109 58.64 59.01 6.29 6.24 10.13 10.19                                         110 56.17 55.96 5.66 5.57 9.73 9.67                                           111 58.10 57.97 6.07 6.16 8.99 9.01                                           112 60.32 60.45 5.45 5.53 8.32 8.55                                           126 52.68 53.06 4.74 4.88 11.62 11.78                                         128 49.59 49.14 4.55 4.56 12.52 12.07                                         129 56.84 57.32 5.35 5.47 12 12.15                                            135 52.01 52.82 5.25 5.2 10.58 10.71                                          136 60.94 62.08 5.86 5.99 13.96 14.48                                         137 55.9 56.02 4.89 4.95 13.67 13.75                                          138 61.74 62.08 5.96 5.99 14.26 14.48                                         139 58.56 58.68 5.52 5.44 14.62 14.41                                         141 58.28 58.38 5.13 5.16 14.22 14.33                                         142 48.88 49.2 4.7 4.78 12.37 12.08                                           145 56 56.02 5.07 4.95 13.87 13.75                                            146 43.36 45.39 4.85 4.61 10.11 8.36                                          147 58.93 59.38 5.75 5.66 12.35 12.59                                       ______________________________________                                    

C. Pharmacological Example EXAMPLE C.1

In vitro binding affinity for dopamine D₄ receptor

The interaction of the compounds of formula (I) with the dopamine D₄receptors was assessed in in vitro radioligand binding experiments. Alow concentration of ³ H-spiperone with a high binding affinity for thedopamine D₄ receptor was incubated with a sample of a membranepreparation of transfected Chinese Hamster Ovary (CHO) cells whichexpress cloned human D₄ receptors (Receptor Biology, Maryland, USA) in abuffered medium. When equilibrium of binding was reached, the receptorbound radioactivity was separated from the non-bound radioactivity, andthe receptor bound activity was counted. The interaction of the testcompounds, added to the incubation mixture in various concentrations,with the dopamine D₄ receptor was assessed in competition bindingexperiments as described by Schotte et al. (Psychopharmacology, 1996,124, 57-73). The compounds with number 2 to 4, 6, 8 to 19, 21, 23, 25,100, 101, 106, 117 to 126, 119, 128 to 130, 134 and 136 to 147 had apIC₅₀ greater than or equal to 7 (pIC₅₀ is defined as -log IC₅₀ whereinIC₅₀ is the concentration of the test compound causing an inhibition of50% of the dopamine D₄ receptors). The remaining compounds which wereprepared in the experimental part were either not tested or had a pIC₅₀of less than 7.

D. Composition Examples

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable addition saltor a stereochemically isomeric form thereof.

EXAMPLE D.1

Capsules

20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose,0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate arevigorously stirred together. The resulting mixture is subsequentlyfilled into 1000 suitable hardened gelatin capsules, each comprising 20mg of the A.I.

EXAMPLE D.2

Film-coated tablets

Preparation of tablet core: A mixture of A.I. (100 g), lactose (570 g)and starch (200 g) is mixed well and thereafter humidified with asolution of sodium dodecyl sulfate (5 g) and polyvinylpyrrolidone (10 g)in water (200 ml). The wet powder mixture is sieved, dried and sievedagain. Then there are added microcrystalline cellulose (100 g) andhydrogenated vegetable oil (15 g). The whole is mixed well andcompressed into tablets, giving 10.000 tablets, each comprising 10 mg ofthe active ingredient. Coating To a solution of methyl cellulose (10 g)in denaturated ethanol (75 ml) there is added a solution of ethylcellulose (5 g) in dichloromethane (150 ml). Then there are addeddichloromethane (75 ml) and 1,2,3-propanetriol (2.5 ml). Polyethyleneglycol (10 g) is molten and dissolved in dichloromethane (75 ml). Thelatter solution is added to the former and then there are addedmagnesium octadecanoate (2.5 g), polyvinylpyrrolidone (5 g) andconcentrated colour suspension (30 ml) and the whole is homogenated. Thetablet cores are coated with the thus obtained mixture in a coatingapparatus.

EXAMPLE D.3

Oral solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3l of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

EXAMPLE D.4

Injectable solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 l of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I.The solution was sterilized by filtration and filled in sterilecontainers.

What is claimed is:
 1. A compound having the formula ##STR19## a N-oxideform, a pharmaceutically acceptable acid addition salt or astereochemically isomeric form thereof, whereinX is O or S; n is 2, 3, 4or 5; R¹ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxy or halo; R² is hydrogen,C₁₋₆ alkyl, phenyl, phenylC₁₋₆ alkyl or phenylcarbonyl; R³ and R⁴ eachindependently are selected from hydrogen, halo, nitro, C₁₋₆ alkyl, C₁₋₆alkyloxy, haloC₁₋₆ alkyl, aminosulfonyl, mono- or di(C₁₋₄alkyl)aminosulfonyl; or R³ and R⁴ may also be taken together to form abivalent radical of formula --CH═CH--CH═CH--.
 2. A compound according toclaim 1 wherein n is 2, 3 or
 4. 3. A compound according to claim 1wherein X is S and R² is hydrogen, C₁₋₆ alkyl, phenyl or phenylC₁₋₆alkyl.
 4. A compound according to claim 1 wherein R² and R³ are hydrogenand R⁴ is chloro.
 5. A compound according to claim 1 wherein thecompoundisN-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine;N-[2-(4-phenyl-1-piperazinyl)ethyl]-2-benzothiazolamine;N-[2-[4-(4-chlorophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine;N-[2-[4-(4-bromophenyl)-1-piperazinyl]ethyl]-2-benzothiazolamine; aN-oxide, a stereoisomeric form or a pharmaceutically acceptable acidaddition salt thereof.
 6. A pharmaceutical composition comprising apharmaceutically acceptable carrier and, as active ingredient, aneffective dopamine D₄ receptor antagonizing amount of a compound asdescribed in claim
 1. 7. A process of preparing a pharmaceuticalcomposition comprising intimately mixing a pharmaceutically acceptablecarrier with an effective dopamine D₄ receptor antagonizing amount of acompound as described in claim
 1. 8. A process of preparing a compoundas described in claim 1, characterized bya) N-alkylating an intermediateof formula (III) ##STR20## wherein n and R² to R⁴ are defined as inclaim 1, with an intermediate of formula (II) ##STR21## wherein Wrepresents an appropriate reactive leaving group, and X and R¹ aredefined as in claim 1, in a reaction-inert solvent, optionally in thepresence of a suitable base, and optionally in the presence of acatalyst; b) reacting an intermediate of formula (III) ##STR22## whereinn and R² to R⁴ are defined as in claim 1, with an intermediate offormula (IV) ##STR23## wherein R¹ is defined as in claim 1, in areaction-inert solvent and in the presence of thionylchloride; thusforming a compound of formula (I-a) ##STR24## c) N-alkylating anintermediate of formula (VI) ##STR25## wherein R³ and R⁴ are defined asin claim 1, with an intermediate of formula (VII) ##STR26## wherein R¹,R², n and X are defined as in claim 1 and W² is an appropriate leavinggroup, in a reaction-inert solvent; d) N-alkylating an intermediate offormula (XV) ##STR27## wherein X, R¹ and R² are defined as in claim 1,with an intermediate of formula (XVI) ##STR28## wherein n, R³ and R⁴ aredefined as in claim 1 and W² is an appropriate leaving group, in areaction-inert solvent, in the presence of a suitable base; e) andfurther, if desired, converting the compounds of formula (I), into atherapeutically active non-toxic acid addition salt by treatment with anacid, or conversely, converting the acid addition salt form into thefree base by treatment with alkali; and, if desired, preparingstereochemically isomeric forms or N-oxides thereof.
 9. A method oftreating a warm-blooded animal suffering from a psychotic disordercomprising administering to the warm-blooded animal a dopamine D₄receptor antagonizing amount of the compound of claim
 1. 10. The methodof claim 9, wherein the pyschotic disorder is schizophrenia.